Riboflavin for the treatment of ischemic stroke and/or other glutamate excitotoxicity-associated diseases

Abstract

The present invention relates to a combination therapy comprising the use of riboflavin and oxaloacetate. Specifically, it is directed to new compositions, pharmaceutical compositions, kits of parts and methods for treating ischemic stroke and/or other excitotoxicity-associated diseases. It further relates to riboflavin for use in the therapeutic treatment of acute ischemic stroke by intravascular administration within the first twelve hours of symptom onset.

1 . Riboflavin for use in the treatment of cerebral ischaemia or traumatic brain injury in a subject, in combination with oxaloacetate and/or diethyloxaloacetate, wherein said treatment is a prophylactic treatment before the clinical onset of the disease or a therapeutic treatment after the clinical onset of the disease; and wherein combination is herein understood as the simultaneous or sequential administration of riboflavin and oxaloacetate and/or diethyloxaloacetate to said subject. 
     
     
         2 . Riboflavin for use according to  claim 1 , wherein riboflavin and oxaloacetate and/or diethyloxaloacetate are administered in a sole pharmaceutical composition or in separate pharmaceutical compositions. 
     
     
         3 . Riboflavin for use according to any of  claims 1  to  2 , wherein riboflavin and oxaloacetate and/or diethyloxaloacetate administration is carried out simultaneously, preferably in a single dose via intravascular bolus injection. 
     
     
         4 . Riboflavin for use according to any of  claims 1  to  3 , wherein the combination is in a dosage capable of providing a neuroprotective effect in the absence of toxic effects associated to succinate dehydrogenase inhibition. 
     
     
         5 . Riboflavin for use according to any of  claims 1  to  4 , wherein riboflavin is administered at a dosage from 0.07 mg/kg to 0.71 mg/kg, preferably from 0.14 mg/kg to 0.42 mg/kg, more preferably from 0.14 mg/kg to 0.28 mg/kg or from 0.16 mg/kg to 0.24 mg/kg. 
     
     
         6 . Riboflavin for use according to any of  claims 1  to  5 , wherein oxaloacetate and/or diethyloxaloacetate is administered at a dosage of below 4 mg/kg, preferably below 3 mg/kg, more preferably below 2.5 mg/kg. 
     
     
         7 . Riboflavin for use according to any of  claims 1  to  6 , wherein the cerebral ischaemia is acute ischemic stroke and the combination is administered within the first twelve hours of symptom onset, preferably within the first six hours, more preferably within the first three hours. 
     
     
         8 . A pharmaceutical composition suitable for intravascular administration comprising riboflavin and oxaloacetate and/or diethyloxaloacetate, wherein said pharmaceutical composition is a sole pharmaceutical composition and wherein the dosage of oxaloacetate and/or diethyloxaloacetate present in said composition is from 2.0 mg/kg to 2.5 mg/kg and wherein the dosage of riboflavin present in said composition is from 0.07 mg/kg to 0.71 mg/kg. 
     
     
         9 . The pharmaceutical composition according to  claim 8  wherein said composition further comprises a pharmaceutically acceptable carrier, additive and/or excipient. 
     
     
         10 . A kit of parts comprising at least two recipients wherein one of the recipients comprises a composition comprising riboflavin, and the other recipient a composition comprising oxaloacetate and/or diethyloxaloacetate, together with instructions for use in the treatment of a disease involving the simultaneous or sequential administration of both active ingredients and wherein the dosage of oxaloacetate and/or diethyloxaloacetate is from 2.0 mg/kg to 2.5 mg/kg and wherein the dosage of riboflavin is from 0.07 mg/kg to 0.71 mg/kg. 
     
     
         11 . The pharmaceutical composition according to  claim 8  or  9  or the kit of parts according to  claim 10  for use in the treatment of cerebral ischaemia or traumatic brain injury in a subject. 
     
     
         12 . A pharmaceutical composition comprising a dosage of riboflavin from 0.07 mg/kg to 0.71 mg/kg, for use in the therapeutic treatment of acute ischemic stroke by intravascular administration to a subject suffering or suspected to suffer from acute ischemic stroke within the first twelve hours of symptom onset. 
     
     
         13 . The pharmaceutical composition for use according to  claim 12 , wherein said subject has not been treated with a reperfusion therapy, preferably with thrombolytic agent recombinant tissue plasminogen activator (rtPA), within the the first twelve hours of symptom onset, preferably within the first 4.5 hours of symptom onset.